Ligands of the tumor necrosis factor (TNF) superfamily have important roles in normal development processes including apoptosis, regulation of immune cell functions and other cell type-specific responses. They also play a significant role in various acquired and genetic diseases, including cancer and autoimmune diseases.
The TNF ligand family is characterized by a conserved extracellular C-terminal domain referred to as TNF homology domain (THD) (Bodmer, J. L. et al. (2002), TRENDS in Biochemical Sciences, 27(1):19-26). The THDs, which share a virtually identical tertiary fold and exhibit a sequence identity between family members of approx. 20 to 30%, are responsible for receptor binding and non-covalently interact to form (homo-)trimeric complexes which are then recognized by their specific receptors. Although most ligands are synthesized as membrane-bound proteins, more specifically type II (i.e., intracellular N-terminus and extracellular C-terminus) transmembrane proteins, soluble cytokines can be generated by proteolytic cleavage of the extracellular domains comprising the THD (Bodmer, J. L. et al. (2002), TRENDS in Biochemical Sciences, 27(1):19-26).
It was an object of the present invention to provide multifunctional, in particular bifunctional or dual-acting, cytokine fusion proteins comprising at least two different cytokines. It was a further object of the present invention to provide nucleic acid molecules, in particular RNA molecules, encoding such cytokine fusion proteins.